OX40 is a T cell co-stimulatory receptor that can enhance the magnitude and durability of T cell immune responses. Anti-OX40 agonist antibodies have shown significant single agent tumoricidal activity in preclinical models, and can combine effectively with other immunomodulatory antibodies, targeted therapies and vaccines. OX40 agonists are able to counteract the immunosuppressive tumor microenvironment and promote tumor-specific cellular immunity via at least two distinct mechanisms: 1) promoting OX40 forward signaling in tumor-specific T cells; and 2) co-engaging Fcγ receptors expressed by tumor-associated effector cells, and facilitating the selective elimination of OX40high intratumoral regulatory T cells. INCAGN1949, an anti-OX40 human IgG1 antibody, was selected based on its ability to optimally enhance T cell responsiveness under conditions of suboptimal T cell receptor stimulation. INCAGN1949 was shown to mediate effective apical OX40 clustering that is translated into effective downstream activation of the NFκB pathway. Notably, INCAGN1949 was shown to maintain a sigmoidal dose response curve across a broad range of antibody concentrations. This suggests a wide therapeutic window and may be advantageous for dosing considerations. By contrast, evaluation of reference OX40 antibodies indicated an inverted U-shaped dose response curve, leading to impaired T cell responses at high concentrations. INCAGN1949 was selected for clinical development based on its optimal agonist profile, further reinforced by its ability to combine with other co-inhibitory and co-stimulatory antibodies to augment T cell responsiveness. Prior to human testing, the pharmacology and tolerability of INCAGN1949 was evaluated in non-human primates (NHPs). Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were evaluated including longitudinal measurements of serum cytokines, immune cell populations, activation state and T cell-mediated immune responses to reporter vaccine antigens. INCAGN1949 exhibited a linear PK profile and was well tolerated at all doses tested, with no maximum tolerated dose established. Co-administration of INCAGN1949 and vaccines in NHPs showed an immune-based PD signature across a broad exposure range. These studies were in line with in vitro findings and support a wide PD range for INCAGN1949 in patients. An important secondary mechanism of INCAGN1949 is the ability of its IgG1 Fc region to mediate selective depletion of OX40high intratumoral regulatory T cells. Immunohistochemistry and flow cytometry analyses support the validity of this regulatory T cell depletion mechanism in a range of tumors. The functional in vitro and in vivo attributes of INCAGN1949 make it suitable for clinical development. It is currently under evaluation in a Phase 1/2 study in subjects with advanced or metastatic tumors (NCT02923349).

Citation Format: Ana M. Gonzalez, Mariana L. Manrique, Lukasz Swiech, Thomas Horn, Ekaterina Breous, Jeremy Waight, David Savitsky, Yuqi Liu, Shiwen Lin, Christopher Clarke, Taha Merghoub, Daniel Hirschhorn-Cymerman, David Schaer, Gerd Ritter, Jennifer Pulini, Kevin Heller, Peggy Scherle, Gregory Hollis, Reid Huber, Marc van Dijk, Jennifer Buell, Robert Stein, Nicholas Wilson. INCAGN1949, an anti-OX40 antibody with an optimal agonistic profile and the ability to selectively deplete intratumoral regulatory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4703. doi:10.1158/1538-7445.AM2017-4703